Abstract 2679: Synergistic effects of the combination of Kras (G12C) with SHP2, ERK 1/2, mTORC1/2 or XPO1 inhibition for the treatment of Kras (G12C) mutated cancer
Authors: Jian Wang, Peng Chen, Ya Kong, Hui Yuwen, Bin Jiang, Linjie Tian, Bing Hou, Jay Mei, Bo Shan
Journal: Cancer Research (2022)

Abstract Background: RAS proteins play a vital role in cellular proliferation, differentiation, and survival, through their association and crosstalk with multiple pathways, the best characterized of which are the Ras/Raf/Mek/Erk and PI3K/PTEN/Akt/mTOR pathways. Activating mutations in KRAS are a hallmark of cancer. Clinical targeting of KRAS G12C mutation has demonstrated profound overall response rate (ORR) with relatively short progression-free survival (PFS). Some potential reasons for short PFS are MAPK pathway re-activation through wild type RAS and activation of PI3K/mTOR pathway, which lead to the bypass and acquired resistance to KRAS G12C inhibitors. The combination of KRAS G12C inhibitor with mTOR or ERK1/2 inhibitor might overcome drug resistance and prolong PFS. This study tested the antitumor effects induced by the combination of ATG-012, a KRAS G12C inhibitor, with SHP2 inhibitor (ET0038), ERK 1/2 kinase inhibitor (ATG-017), mTORC1/2 kinase inhibitor (ATG-008) or XPO1 inhibitor (selinexor), in preclinical tumor models. Methods: The in vivo combinations of the drugs were tested in NCI-H358 (non-small cell lung cancer) and Mia-Paca-2 (pancreatic cancer) CDX mouse model. The tumor bearing mouse were treated with vehicle control, ATG-012 (3 to 100 mg/kg, QD), ET0038 (5mg/kg, QD), selinexor (10mg/kg, MWF), ATG-017 (25mg/kg, QD), ATG-008 (10mg/kg, QD) or the combination for 18 to 27 days. Tumor size was measured twice a week and tumor growth inhibition (TGI) was evaluated compared with vehicle control group. Results: In the NCI-H358 CDX in vivo study, mono therapy with ATG-012 (10mg/kg), selinexor, or ATG-017 induced tumor growth inhibition (TGI) of 44.29%,73.71% and 80.85%, respectively on day 8 after grouping. The combination of ATG-012 and selinexor showed 84.96% TGI, while ATG-012 plus ATG-017 showed 97.13% TGI. The combinations induced continual tumor regression from day 9 to day 21.In the Mia-PaCa-2 CDX in vivo study, the mono therapy with ATG-012 (3 mg/kg) showed 65.6% TGI on day 27 after grouping, while single agent ET0038 or ATG-008 treatment induced 84.6% and 75.4% TGI, respectively. The combination of ATG-012 and ET0038 showed 119.1% TGI; and ATG-012 -ATG-008 combination showed 92.3% TGI. Conclusions: Strong in vivo synergism has been observed for the combination of a Kras (G12C) inhibitor (ATG-012) with a SHP2 inhibitor, ERK 1/2 inhibitor, mTORC1/2 inhibitor or XPO1 inhibitor, suggesting promising clinical therapeutic strategies for cancer patients carrying the KRAS G12C mutation. Citation Format: Jian Wang, Peng Chen, Ya Kong, Hui Yuwen, Bin Jiang, Linjie Tian, Bing Hou, Jay Mei, Bo Shan. Synergistic effects of the combination of Kras (G12C) with SHP2, ERK 1/2, mTORC1/2 or XPO1 inhibition for the treatment of Kras (G12C) mutated cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2679.